Iron Restriction to Clinical Isolates of Candida Albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles In Vitro and In Vivo in a Murine Model of Experimental Vaginitis

Iron Restriction to Clinical Isolates of Candida Albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles In Vitro and In Vivo in a Murine Model of Experimental Vaginitis

Abstract

Candida albicans is an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S. CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells, and there is growing evidence that interference with iron homeostasis of C. albicans can improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates of C. albicans DIBI, but not deferoxamine or deferiprone, inhibited the growth of C. albicans at relatively low concentrations in vitro, and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged the inhibition of cell multiplication. In addition, the administration of DIBI along with fluconazole (FLC) to mice inoculated with an FLC-sensitive isolate in a model of experimental C. albicans vaginitis showed a markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.

Recovery growth of C. albicans is inhibited after exposure to a combination of…

FIG 3

Recovery growth of C. albicans is inhibited after exposure to a combination of fluconazole (FLC) and DIBI. A 5-μl volume from each well of a checkerboard assay that had been inoculated with Ca5031 was spotted onto a YPD agar plate following 24-h (A) or 48-h (B) exposure to the agent. Recovery plates were incubated for 24 h before being visually inspected and photographed. Images are representative of results observed in 3 independent experiments.

FIG 4

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Long-term growth inhibition of C.…

FIG 4

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Long-term growth inhibition of C. albicans by combinations of DIBI with fluconazole (FLC),…